Borane reagents such as borane-tetrahydrofuran complex (sometimes referred to as THFB) are valuable reagents for the reduction of functional groups and for hydroboration reactions with carbon-carbon double and triple bonds. For example, functional groups reduced by borane-tetrahydrofuran complex include aldehyde, ketone, acyl chloride, lactone, epoxide, ester, amide, oxime, imine, and nitrile. Borane-tetrahydrofuran complex is a very selective and clean reducing agent. Because the borane is complexed to the low-boiling (65.degree. C.), common solvent, tetrahydrofuran, no byproduct residues are generated. Typically a reduction is quenched with excess methanol to deactivate any remaining borane-tetrahydrofuran complex and distilled to remove the boron from the desired products as the methylborate/methanol azeotrope.
The enantioselective reduction of prochiral ketones with borane-tetrahydrofuran complex in the presence of an oxazaborolidine chiral catalyst such as (R)-MeCBS (a methyl-substituted chiral oxazaborolidine named after Corey, Bakshi, and Shibata) is a very important tool for the synthesis of alcohols in high optical purity. See, for example, Corey, E. J. and Helel, C. J., "Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method," Angew. Chem. Int. Ed., 37, 1986-2012 (1998); U.S. Pat. No. 4,943,635; and Franot, C. et al., A Polymer-Bound Oxazaborolidine Catalysts: "Enantioselective Borane Reductions of Ketones," Tetrahedron: Asymmetry, 6:11, 2755-2766 (1995).
However, the selectivity of the reaction has been found to be affected by a number of parameters including, for example, temperature and borane source/batch. In that regard, the enantioselectivity of (R)-MeCBS catalyzed reductions has been found to be quite low for various commercial samples of THFB. Several researchers have presumed that the widely variable results achieved with commercially available THFB were a result of decomposition thereof. See Jones, T. K. et al., "An Asymmetric Synthesis of MK-0417. Observations on Oxazaborolidine-Catalyzed Reductions," J. Org. Chem., 56, 763-769 (1991).
In that regard, although THFB is a very valuable reagent, THFB complexes are known to decompose during transportation and storage at ambient temperature and to thermally decompose during reaction. To prevent decomposition during transportation and storage, stabilizers are typically added to borane-tetrahydrofuran complex. Typically, a hydride source such as a metal hydride (for example, potassium hydride, sodium hydride or lithium hydride) or sodium borohydride (NaBH.sub.4) is added to THFB. Sodium borohydride and other hydrides have been shown to be quite effective in stabilizing THFB. At least one study has also shown that sodium borohydride leads to strongly enhanced activity in the reduction of ketones. Jockel, H. and Schmidt, R., "Kinetics of Direct Borane Reduction of Pinacolone in THF," J. Chem. Soc., Perkin Trans. 2, 2719-2723 (1997). Other borohydride sources include, for example, potassium borohydride, lithium borohydride, and tetraalkylammonium borohydride. Moreover, metal alkoxides (for example, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amylate, potassium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide, sodium methoxide, potassium methoxide and lithium methoxide) can be added to generate a borohydride stabilizing agent within THFB.
It is very desirable to develop borane compositions and methods of reaction that improve enantioselectivity.